The existence of an endogenous cannabinoid system, comprising cannabinoid receptors and endogenous ligands is now well recognized. However, the distribution of cannabinoid receptors and the impact of cannabinoid agonists on monoaminergic neurotransmitter systems is only slowly beginning to emerge. This information is essential for understanding cellular adaptations following chronic recreational drug exposure as well as elucidating potential therapeutic uses for cannabinoid-based compounds. Acute effects of cannabinoid receptor agonist administration include deficits in learning and memory, distorted perception, difficulty in problem solving and loss of coordination. Repeated administration leads to increases in the activation of the stress-response system, anxiety, depression, cognitive impairment, and psychosis. The question remains as to where cannabinoids act to induce cellular adaptations that may result in long term behavioral dysfunction. Preliminary data from our laboratories suggest that one potential target is the noradrenergic coeruleo-cortical pathway, a biogenic amine system involved in modulating higher cognitive function and mood. This system is implicated in setting the attentional mode, and is engaged as part of the stress response to facilitate arousal. Our guiding hypothesis is that chronic cannabinoid administration results in a potentiated noradrenergic system that may contribute to the pathophysiology of affective disorders. The proposed aims, which integrate neuroanatomical, neurochemical and behavioral approaches, promise to further our understanding of the cellular substrates for cannabinoid receptor modulation of the locus coeruleus (LC)-frontal cortex pathway and reveal the participation of this circuit in cannabinoid-induced anxiety. Four specific aims are proposed to answer the following questions: 1) What are the cellular sites mediating cortical norepinephrine efflux induced by cannabinoids ? 2) What is the neuroanatomical distribution of CB1 receptors in the frontal cortex and LC ? 3) Does repeated administration of cannabinoid agonists result in long term effects on noradrenergic function (as detected by increases in tyrosine hydroxylase gene express and release) 4) What are the effects of noradrenergic lesions on cannabinoid-induced anxiety ? By accomplishing the proposed specific aims, we will have a firm understanding of the cellular sites of action of cannabinoids on brain noradrenergic function and the behavioral consequences of chronic exposure to cannabinoids on the noradrenergic system.